Tapering Schedule Research Articles

A Digital Intervention for Primary Care Practitioners to Support Antidepressant Discontinuation (Advisor for Health Professionals): Development Study.

BackgroundThe number of people receiving antidepressants has increased in the past 3 decades, mainly because of people staying on them longer. However, in many cases long-term treatment is not evidence based and risks increasing side effects. Additionally, prompting general practitioners (GPs) to review medication does not improve the rate of appropriate discontinuation. Therefore, GPs and other health professionals may need help to support patients discontinuing antidepressants in primary care.ObjectiveThis study aims to develop a digital intervention to support practitioners in helping patients discontinue inappropriate long-term antidepressants (as part of a wider intervention package including a patient digital intervention and patient telephone support).MethodsA prototype digital intervention called Advisor for Health Professionals (ADvisor HP) was planned and developed using theory, evidence, and a person-based approach. The following elements informed development: a literature review and qualitative synthesis, an in-depth qualitative study, the development of guiding principles for design elements, and theoretical behavioral analyses. The intervention was then optimized through think-aloud qualitative interviews with health professionals while they were using the prototype intervention.ResultsThink-aloud qualitative interviews with 19 health professionals suggested that the digital intervention contained useful information and was readily accessible to practitioners. The development work highlighted a need for further guidance on drug tapering schedules for practitioners and clarity about who is responsible for broaching the subject of discontinuation. Practitioners highlighted the need to have information in easily and quickly accessible formats because of time constraints in day-to-day practice. Some GPs felt that some information was already known to them but understood why this was included. Practitioners differed in their ideas about how they would use ADvisor HP in practice, with some preferring to read the resource in its entirety and others wanting to dip in and out as needed. Changes were made to the wording and structure of the intervention in response to the feedback provided.ConclusionsADvisor HP is a digital intervention that has been developed using theory, evidence, and a person-based approach. The optimization work suggests that practitioners may find this tool to be useful in supporting the reduction of long-term antidepressant use. Further quantitative and qualitative evaluation through a randomized controlled trial is needed to examine the feasibility, effectiveness, and cost-effectiveness of the intervention.

Safety and Efficacy of Extracorporeal Photopheresis for Acute and Chronic Graft-Versus-Host-Disease

IntroductionAcute and chronic graft-versus-host disease (GVHD) remain severe complications of allogeneic hematopoietic cell transplantation (alloHCT). Corticosteroids and conventional intensified immunosuppressive therapy for steroid-refractory GVHD increase morbidity, mortality and relapses without improving survival. Extracorporeal photopheresis (ECP) has been introduced as an alternative treatment in many centers. We studied the safety and efficacy of extracorporeal photopheresis (ECP) as second or third line treatment in acute and chronic GvHD.MethodsWe enrolled consecutive patients that received ECP post alloHCT from 2003 to 2016. All patients with unrelated or haploidentical donors received thymoglobulin (ATG) 5mg/kg as prophylaxis. GVHD prophylaxis included cyclosporine-methotrexate in myeloablative and cyclosporine-mycophenolate mofetil in reduced toxicity or intensity regimens. ECP was commenced after assessment of response to 7 days of steroid treatment in acute (aGVHD): 2 sessions/week for 1 month, 1 session/2 weeks for 3 months, evaluation of response and 1 session/month for 6 months. In chronic (cGVHD), ECP was mostly administered as third line treatment with a similar protocol that was less intensified in the 1st month (1 session/week).ResultsWe studied 21 patients with acute, 81 with chronic and 7 with induced GVHD post Donor Lymphocyte Infusion (DLI) for relapsed disease. Only 2 patients with acute, 5 with chronic and 1 with induced GVHD received 4 or less ECP sessions because of severe GVHD-related morbidity and were excluded from further analysis. There were no ECP-related adverse events.AGVHD was observed at day +18 (8-50) in 15 patients, late-onset at + 130 (110-160) in 4 patients. Skin, intestine and liver involvement was evident in 6 patients, skin and intestine in 9 and skin only in 4 patients. Seven patients were steroid-dependent and 12 steroid-refractory. ATG was administered simultaneously with ECP initiation in 8 refractory patients. The majority of patients presented partial (6), very good (9) or complete (1) response to ECP. Immunosuppression was reduced in 10/19 and ceased in 1. Clinically significant bacterial infections were found in 17 patients, fungal in 2 and viral in 15 patients. Cumulative incidence (CI) of cGVHD was 86.6 at 1-year. 1-year CI of aGVHD-related mortality was 17.6% and was associated with lack of response to ECP (p=0.026) and steroid-refractoriness (p<0.001). With a follow-up of 17.5 (1.8-58.3) months, 1-year overall survival (OS) was 52.5%. Improved OS was associated with response to ECP (0.032), number of ECP sessions (p=0.005), aGVHD grade (p=0.018) and reduction of immunosuppression (p=0.009). In the multivariate analysis, number of ECP sessions were independently associated with improved OS (p=0.037).Regarding cGVHD, 52 patients presented with cutaneous sclerosis manifestations, 53 mucocutaneous disease, 31 liver, 37 visceral and 12 lung involvement. The majority of them (59/82) received mycophenolate mofetil, cyclosporine or ATG as a second line treatment and ECP as third line. Bacterial infections were observed in 26 patients, viral in 24 and fungal in 8 patients. Eligible for evaluation of response were 72 patients. Only 12 patients did not show response. Significantly higher rates of response presented in patients with cutaneous sclerosis manifestation (p=0.031) and later post-transplant GVHD diagnosis (p=0.001). With a follow-up of 68.1 (5.4-283.1) months, 5-year CI of cGVHD-related mortality was 24.1% and was associated only with number of ECP sessions (p=0.002). 5-year OS was 64.5% and was associated with HLA matching (p=0.030), cutaneous lesions (p=0.041), higher number of ECP sessions (p<0.001), later initiation of ECP post-transplant (p=0.004) and no relapse (p=0.027). In the multivariate analysis, cutaneous lesions (p=0.013), number of ECP (p<0.001) and days of ECP initiation post-transplant (p=0.015) predicted OS.ConclusionOur data indicate that ECP is safe and effective for both acute and chronic GVHD. Steroid-dependence in aGVHD and cutaneous manifestations in cGVHD predict improved survival with low toxicity. Therefore, ECP should be considered early in the course of GVHD, before significant irreversible end organ damage has been established. Optimal timing of intervention, frequency, duration and tapering schedule of ECP remain important unanswered questions. DisclosuresGavriilaki:European Hematology Association: Research Funding.

Rituximab versus Mycophenolate Mofetil in Patients with Pemphigus Vulgaris

BackgroundRituximab and mycophenolate mofetil are used to treat pemphigus vulgaris, but they have not been adequately compared in clinical trials.MethodsIn a randomized, controlled trial, we assigned patients with moderate-to-severe pemphigus vulgaris in a 1:1 ratio to receive intravenous rituximab (1000 mg on days 1, 15, 168, and 182) or oral mycophenolate mofetil (2 g per day), in addition to an oral glucocorticoid administered on the same tapering schedule in the two groups. The primary end point was sustained complete remission at week 52, defined as the healing of lesions with no new active lesions, as reflected by a Pemphigus Disease Area Index (PDAI) activity score of 0 (on a scale of 0 to 250, with higher scores indicating greater disease severity), for at least 16 weeks without the use of glucocorticoids. Secondary end points were the cumulative dose of glucocorticoids, the number of disease flares, and the change from baseline in the score on the Dermatology Life Quality Index (DLQI; scores range from 0 to 30, with higher scores indicating greater impairment).ResultsOf the 135 patients who underwent randomization, 67 were assigned to receive rituximab and 68 to receive mycophenolate mofetil. The primary outcome was assessed in the modified intention-to-treat population: 62 patients in the rituximab group and 63 in the mycophenolate mofetil group. The median PDAI activity scores at baseline were 22.7 in the rituximab group and 18.3 in the mycophenolate mofetil group. At week 52, sustained complete remission was observed in 25 patients (40%) in the rituximab group and in 6 (10%) in the mycophenolate mofetil group (difference, 31 percentage points; 95% confidence interval [CI], 15 to 45; P<0.001). The mean cumulative glucocorticoid dose during the 52-week treatment period was 3545 mg in the rituximab group and 5140 mg in the mycophenolate mofetil group (difference, −1595 mg; 95% CI, −2838 to −353; P<0.001). There were 6 disease flares in the rituximab group and 44 in the mycophenolate mofetil group (adjusted rate ratio, 0.12; 95% CI, 0.05 to 0.29; P<0.001). The mean change in DLQI score was −8.87 points and −6.00 points, respectively (difference, −2.87 points; 95% CI, −4.58 to −1.17; P=0.001). Serious adverse events occurred in 15 of 67 patients (22%) in the rituximab group and in 10 of 68 (15%) in the mycophenolate mofetil group.ConclusionsRituximab was superior to mycophenolate mofetil in producing sustained complete remission at 52 weeks in patients with pemphigus vulgaris. Rituximab resulted in a greater reduction in glucocorticoid use than mycophenolate mofetil, but more patients in the rituximab group had serious adverse events. Further trials are needed to determine the comparative efficacy and safety of rituximab and mycophenolate mofetil beyond 52 weeks of treatment. (Funded by F. Hoffmann–La Roche; PEMPHIX ClinicalTrials.gov number, NCT02383589.)

Predictive Accuracy of Delta Cortisol on Recovery of Adrenal Function in Patients With Drug Induced Cushing’s Syndrome With Secondary Adrenal Insufficiency

There is a growing concern upon the finding of many drug induced Cushing’s syndrome because of inadvertent use of glucocorticoids (GC) either prescribed or as alternative medicine in Myanmar. These patients are presenting with diversity of clinical problems ranging from hypertension, diabetes to acute adrenal crisis due to hypothalamic-pituitary-adrenal (HPA) axis suppression and secondary adrenal insufficiency (AI). The present study aimed to assess the delta cortisol (the degree of cortisol increments) during the first short Synacthen test (SST) as a factor predictive of adrenal function recovery in patients with drug induced Cushing’ syndrome with secondary AI and to determine the proportion of patients who recovered from AI within six-month follow-up. This was a hospital based prospective analytical study that enrolled a total of 52 patients with drug induced Cushing’s syndrome with secondary AI from January 2018 to June 2019. Secondary AI is defined by morning basal serum cortisol ≤ 400 nmol/L with Synacthen stimulated peak cortisol level ≤ 550 nmol/L and serum ACTH < 60 pg/ml. The follow-up SSTs were performed at three-month and six-month after first SST, and the patients with morning basal serum cortisol > 400 nmol/L (or) Synacthen stimulated peak serum cortisol > 550 nmol/L during follow-up SSTs are defined as recovered adrenal function group. In this study, a total of 52 patients were treated with modified regimen of physiological dose of prednisolone with tapering schedule or stress dose GC based on the basal serum cortisol levels up to six months. Among them, nearly half (n=25 / 48.1%) of the patients with drug induced Cushing’s syndrome with secondary AI achieved normal adrenal function within six-month follow-up. It was found that mean values for delta cortisol were not statistically significant between recovered and non-recovered groups, 118.6 nmol/L (SD 72.3) and 97.2 nmol/L (SD 64.2) respectively. The delta cortisol during the first SST could not predict strongly (AUC - 0.6, 95% CI - 0.44 to 0.76, P = 0.2) the recovery of adrenal function in patients with drug induced Cushing’s syndrome with secondary AI and it was inconsistent with previous studies. The older age of the patients, oral route of administration of drugs causing Cushing’s syndrome and comorbid hypertension were found to be more significant in the non-recovered group. In conclusion, the present study did not support the evidence that the delta cortisol during the first SST could predict adrenal function recovery in patients with drug induced Cushing’ syndrome with secondary AI. Reference: (1) Baek et al., 2016; Recovery of Adrenal Function in Patients with Glucocorticoids Induced Secondary AI. Endocrinol Metab.31, pp. 153–160. (2) Pofi et al., 2018; The Short Synacthen Test Can Be Used to Predict Recovery of HPA Axis Function. J Clin Endocrinol Metab.103(8), pp. 3050–3059.

P002 Real-world experiences of biologic tapering

Abstract Background/Aims Biologic therapy and treat to target have significantly improved patient outcomes and we now have a proportion of patients on biologic therapy who remain in clinical remission. NICE guidance suggests “cautiously reducing drug doses or stopping drugs in those who have maintained the treatment target”. Despite this guidance, little is known about current clinical practice of biologic tapering in UK rheumatology centres. We aimed to illustrate current practice and success rates in biologic tapering in a real-world setting in patients with rheumatoid arthritis (RA), psoriatic arthritis (PSA) and ankylosing spondylitis (AS). Methods We identified patients who were potentially suitable for biologic tapering 1 week prior to their follow up appointment using the following criteria - any anti-TNFα biologic ≥ 1 year, RA patients (DAS28 CRP&amp;lt;3.2, CRP normal), PSA patients (no swollen joints, CRP normal, no extra-articular manifestations), AS patients (BASDAI&amp;lt;4, CRP normal). We then analysed how many patients were successfully tapered at one year. Tapering schedule was decided by the supervising rheumatologist. Results From December 2018 to February 2019, 66 patients were identified as being suitable for biologic tapering. 3 patients did not attend and were excluded from further analysis. Tapered group: 20 (32%) patients were tapered. Based on the retrospective review of clinic letters, the “tapering schedule” was inconsistent and the information provided to patients if they flared was also inconsistent - 9 (45%) patients were advised to return to their normal dose and only 1 (5%) patient was advised to contact the helpline. After 12 months of follow up, 11 (55%) patients remained on the tapered dose, 7 (35%) patients returned to their prior dose and 2 (10%) patients were lost to follow up. Non-tapered group: 43 (68%) patients were not tapered. The reasons for not tapering were divided into 6 broad categories: active disease (n = 15, 35%), patient choice (n = 5, 12%), DMARD was tapered instead (n = 5, 12%), discuss at next visit (n = 3, 7%), reason not mentioned (n = 12, 28%), other (n = 3, 7%) Conclusion This Quality Improvement Project has highlighted the inconsistencies in biologic tapering in a UK real-world setting. In response to this inconsistency, we have developed a departmental guideline which provides stringent criteria to identify patients at lowest risk of flaring and standardises a tapering schedule and clinical pathway. We also created a patient information leaflet that could be distributed. Only half of the patients remained on the tapered dose after 1 year, suggesting a significant proportion of patients flare following dose reduction. However, our findings may be limited by small sample size. National guidance and a thorough audit based on this guidance is welcomed. Disclosure Z. Rutter-locher: None. Y. Long Man: None. L. Marsh: None. S. Mercer: None. B. Menon: None. A. Cope: None.

Research in Brief

In the phase 3 ADVOCATE trial, David Jayne and colleagues randomly assigned (1:1) 331 patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis to receive the oral C5a receptor inhibitor avacopan (30 mg twice daily) or a tapering schedule of oral prednisone. Remission at week 26 (a Birmingham Vasculitis Activity Score of 0 and no glucocorticoid use in the previous 4 weeks; primary outcome) was achieved by 120 (72·3%) of 166 patients on avacopan versus 115 (70·1%) of 164 on prednisone (estimated common difference 3·4 percentage points [95% CI −6·0 to 12·8]; p<0·001 for noninferiority, p=0·24 for superiority). Sustained remission at week 52 (co-primary outcome) was achieved by 109 (65·7%) on avacopan and 90 (54·9%) on prednisone (estimated common difference 12·5 percentage points [2·6 to 22·3]; p<0·001 for non-inferiority, p=0·007 for superiority). Serious adverse events were similar between groups.

A prospective multi-centre, randomized study comparing the addition of tapering dexamethasone to other standard of care therapies for taxane-associated pain syndrome (TAPS) in breast cancer patients.

Taxane-associated pain syndrome (TAPS) is common with docetaxel and is characterised by myalgias and arthralgias starting 2-3 days after treatment and can last for up to 7 days. Anecdotal evidence suggests that corticosteroids can reduce TAPS. This multicentre, randomized trial evaluated the effect of additional tapering dexamethasone on TAPS. 130 breast cancer patients commencing docetaxel were randomized to dexamethasone premedication (8 mg/twice daily for 3 days) or dexamethasone premedication followed by tapering dexamethasone (4 mg/daily for 2 days followed by 2 mg/daily for 2 days). The primary endpoint was absolute change in FACT-Taxane questionnaire during the first chemotherapy cycle. Secondary endpoints: proportion of patients with clinically significant TAPS, QoL, pain and toxicity. 110/130 patients had complete data included in the primary analysis. The fall in FACT-Taxane scores was lower in the experimental group on day 5 (p = 0.05), but not on day 7 (p = 0.21). There was no difference in FACT-Taxane scores over the entire study duration (p = 0.59). Fewer patients in the experimental arm reported TAPS on day 5 (30 vs. 47%). There was a borderline significant attenuation of impairment of QoL with experimental treatment on day 5 (p = 0.06), but not day 7 (p = 0.53). Tapered schedule was associated with more dyspepsia and insomnia. A tapering schedule of dexamethasone was associated with a brief reduction in docetaxel-associated symptoms which was observed only during dexamethasone exposure and did not persist after discontinuation of the drug. ClinicalTrials.gov NCT03348696.

Avacopan for the Treatment of ANCA-Associated Vasculitis

BackgroundThe C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis.MethodsIn this randomized, controlled trial, we assigned patients with ANCA-associated vasculitis in a 1:1 ratio to receive oral avacopan at a dose of 30 mg twice daily or oral prednisone on a tapering schedule. All the patients received either cyclophosphamide (followed by azathioprine) or rituximab. The first primary end point was remission, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 (on a scale from 0 to 63, with higher scores indicating greater disease activity) at week 26 and no glucocorticoid use in the previous 4 weeks. The second primary end point was sustained remission, defined as remission at both weeks 26 and 52. Both end points were tested for noninferiority (by a margin of 20 percentage points) and for superiority.ResultsA total of 331 patients underwent randomization; 166 were assigned to receive avacopan, and 165 were assigned to receive prednisone. The mean BVAS at baseline was 16 in both groups. Remission at week 26 (the first primary end point) was observed in 120 of 166 patients (72.3%) receiving avacopan and in 115 of 164 patients (70.1%) receiving prednisone (estimated common difference, 3.4 percentage points; 95% confidence interval [CI], −6.0 to 12.8; P<0.001 for noninferiority; P=0.24 for superiority). Sustained remission at week 52 (the second primary end point) was observed in 109 of 166 patients (65.7%) receiving avacopan and in 90 of 164 patients (54.9%) receiving prednisone (estimated common difference, 12.5 percentage points; 95% CI, 2.6 to 22.3; P<0.001 for noninferiority; P=0.007 for superiority). Serious adverse events (excluding worsening vasculitis) occurred in 37.3% of the patients receiving avacopan and in 39.0% of those receiving prednisone.ConclusionsIn this trial involving patients with ANCA-associated vasculitis, avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52. All the patients received cyclophosphamide or rituximab. The safety and clinical effects of avacopan beyond 52 weeks were not addressed in the trial. (Funded by ChemoCentryx; ADVOCATE ClinicalTrials.gov number, NCT02994927.)

Sudden Onset of Myelitis after COVID-19 Vaccination: An Under-Recognized Severe Rare Adverse Event

Myelitis has been reported as a complication of COVID-19 infection. However, it has rarely been reported as a complication of COVID-19 vaccination, and this may be the first case report following an mRNA vaccine. A 63 yo, otherwise healthy male, received his second dose of the Moderna vaccine on 08 April 2021. He had some initial pain and soreness at the injection site. Seventeen hours post dose, he reported pain and numbness in both calves which progressed to lower back pain, paresthesia in both feet, and pain in lower extremities. Over the day post- vaccination the patient’s condition worsened and he was unable to walk and unable to urinate voluntarily. On the second day post- vaccination he presented to the Emergency Department and was admitted to the University of Iowa hospital unable to walk with severe pain in lower back, legs and feet, and numbness in buttocks. Laboratory findings were unremarkable and lumbar puncture was not diagnostic. MRI revealed increased T2 cord signal seen in the distal spinal cord and conus. Initial treatment included IV Immunoglobulin for 2 days, followed by methylprednisolone 1000 mg/day IV for 5 days. Discharge from the hospital occurred on 16 April 2021 to inpatient rehabilitation. Treatment consisted of oral prednisone 60 mg/day with a tapering schedule. The patient slowly improved and was able to ambulate unassisted at 25 days post -vaccination. This case represents one of the first cases of myelitis reported in the literature after COVID-19 mRNA vaccination. As of 27 April 2021 the FDA VAERS system has 45 reports of transverse myelitis after COVID-19 vaccination (21 after Moderna vaccine, 19 were after Pfizer vaccine, and 5 occurred after Janssen vaccine).

Benzodiazepines: Thinking outside the black box

The United States Food and Drug Administration (FDA) recently issued a Drug Safety Communication requiring Boxed Warning updating and other changes in order to improve the safe use of the benzodiazepine drug class. These changes were prompted because 'The current prescribing information for benzodiazepines does not provide adequate warnings about [the] serious risks and harms associated with these medicines so they may be prescribed and used inappropriately'. The FDA Communication points out that benzodiazepines can be an important option for treating disorders for which these drugs are indicated. However, the acknowledged problems of these drugs, which historically were considered an acceptable trade-off against their benefits, need to be reassessed in light of their widespread (over?) prescribing (for example, in 2019 an estimated 92 million benzodiazepine prescriptions were dispensed from US retail and mail-order pharmacies). The FDA Communication can be viewed as an important step in reminding healthcare providers of the 'serious risks and harms associated with these medicines', and validation of such reports by patients. Importantly, the FDA Communication includes an often-neglected aspect of benzodiazepine prescribing, namely how to discontinue use, and the perplexing protracted withdrawal syndrome experienced by some patients. The Communication advises to providers: 'No standard benzodiazepine tapering schedule is suitable for all patients; therefore, create a patient-specific plan to gradually reduce the dosage, and ensure ongoing monitoring and support as needed to avoid serious withdrawal symptoms or worsening of the patient's medical condition'.

Consensus-based recommendations for titrating cannabinoids and tapering opioids for chronic pain control.

AimsOpioid misuse and overuse have contributed to a widespread overdose crisis and many patients and physicians are considering medical cannabis to support opioid tapering and chronic pain control. Using a five‐step modified Delphi process, we aimed to develop consensus‐based recommendations on: 1) when and how to safely initiate and titrate cannabinoids in the presence of opioids, 2) when and how to safely taper opioids in the presence of cannabinoids and 3) how to monitor patients and evaluate outcomes when treating with opioids and cannabinoids.ResultsIn patients with chronic pain taking opioids not reaching treatment goals, there was consensus that cannabinoids may be considered for patients experiencing or displaying opioid‐related complications, despite psychological or physical interventions. There was consensus observed to initiate with a cannabidiol (CBD)‐predominant oral extract in the daytime and consider adding tetrahydrocannabinol (THC). When adding THC, start with 0.5‐3 mg, and increase by 1‐2 mg once or twice weekly up to 30‐40 mg/day. Initiate opioid tapering when the patient reports a minor/major improvement in function, seeks less as‐needed medication to control pain and/or the cannabis dose has been optimised. The opioid tapering schedule may be 5%–10% of the morphine equivalent dose (MED) every 1 to 4 weeks. Clinical success could be defined by an improvement in function/quality of life, a ≥30% reduction in pain intensity, a ≥25% reduction in opioid dose, a reduction in opioid dose to <90 mg MED and/or reduction in opioid‐related adverse events.ConclusionsThis five‐stage modified Delphi process led to the development of consensus‐based recommendations surrounding the safe introduction and titration of cannabinoids in concert with tapering opioids.

EPID-33. PRACTICE VARIATION OF STEROID DOSING AND TAPERING SCHEDULES AMONG THE NEURO-ONCOLOGY COMMUNITY

Abstract INTRODUCTION Steroids are commonly used for treatment of peritumoral edema and increased intracranial pressure in brain tumor patients. However, despite the widespread use of steroids, relatively little evidence is available about the optimal dosing scheme in brain tumor patients. PURPOSE The aim of this study is to increase insight in the practice variation of steroid dosing and tapering schedules among the neuro-oncology community. METHODS An electronic survey consisting of 27 questions regarding dosing and tapering schedules and adverse events of steroids was conducted among neurosurgeons internationally between 6 December 2019 and 1 June 2020. The survey was distributed by the electronic mailing lists of the Europeans Association of Neurosurgical Societies and via social media platforms. Collected data was assessed for quantitative and qualitative analysis using the Kruskal-Wallis test. RESULTS The survey obtained 175 responses. 87% of respondents answered all questions. Steroids are prescribed routinely perioperatively by 80% of respondents. Prescribed doses range from 2 to 64 mg/day in dosing schedule ranging from one to four times a day. The most prescribed steroid is dexamethasone in a dose of 16 mg/day. No significant association is seen between the prescribed dose and frequency of adverse events, years of experience, country, type of institution or having an institutional guideline. CONCLUSION Steroids are routinely prescribed perioperatively in brain tumor patients. However, there is a great practice variation in steroid dosing and tapering schedules among neurosurgeons. Future investigation is needed to identify an optimal dosing scheme and implement (inter)national guidelines for the dosing of steroids.

Results of the PROPINE randomized controlled study suggest tapering of prednisone treatment for relapses of steroid sensitive nephrotic syndrome is not necessary in children

Corticosteroid-related toxicity in children with steroid-sensitive nephrotic syndrome is primarily related to the cumulative dose of prednisone. To optimize treatment of relapses, we conducted the PROPINE study, a multicentric, open-label, randomized, superiority trial. Seventy-eight relapsing children aged 3-17 years who had not received steroid-sparing medications during the previous 12 months were randomized to receive, from day five after remission, either 18 doses of 40 mg/m2 of prednisone on alternate days (short arm), or the same cumulative dose tapered over double the time (long arm). Patients were monitored with an ad-hoc smartphone application, allowing daily reporting. The primary outcome was the six-month relapse rate at which time, 23/40 and 16/38 patients had relapsed in the long and short arms, respectively (no significant difference). Additionally, 40/78 patients were also enrolled in a secondary crossover study and were allocated to the opposite arm. Altogether, at six months, the relapse rate was 32/40 and 28/40 in the long and short arms, respectively (no significant difference). A post-hoc analysis excluding 30 patients treated with low-dose prednisone maintenance therapy failed to show significant differences between the two arms. No differences in adverse events, blood pressure and weight gain were observed. Thus, our data do not support the prescription of prolonged tapering schedules for relapses of steroid-sensitive nephrotic syndrome in children.

Novel Pharmacotherapies for Recurrent Pericarditis: Current Options in 2020.

Recent advances have shown impressive results by anti-interleukin 1 (IL-1) agents in refractory idiopathic recurrent pericarditis.Purpose of ReviewWe critically discuss the current state of the art of therapy of relapsing pericarditis, with a focus on new pharmacological approaches and on specific clinical settings such as pregnancy, pediatric patients, and secondary forms of relapsing pericarditis.Recent FindingsAntagonism of the IL-1 is highly effective in idiopathic recurrent pericarditis with autoinflammatory features. Currently, available anti-IL-1 agents are anakinra and canakinumab. Rilonacept is another IL-1 antagonist, currently studied in the phase-3 clinical trial RHAPSODY. Available data suggest similar efficacy and safety profiles of these three agents, although only anakinra has been tested in randomized clinical trials. These agents have slightly different pharmacological properties, being canakinumab a specific IL-1ß antagonist while anakinra and rilonacept are unselective IL-1α and IL-1ß blockers. To date, there is no evidence that specificity against IL-1ß affects safety and efficacy in patients with relapsing pericarditis, although it has been proposed that unspecific blockage might be useful in severe disease.SummaryAnakinra is the first anti-IL-1 agent with well-documented efficacy and safety in adult and pediatric patients with idiopathic relapsing pericarditis. Other anti-IL-1 agents are currently under study. Future research should clarify the optimal duration of therapy and tapering schedule of treatment with these agents. Moreover, biomarkers would be required to understand which patients will benefit from early administration of IL-1 blockers due to refractoriness to conventional therapy and which others will suffer from recurrences during the tapering of these agents. Lastly, future studies should focus on the subjects with the autoimmune or the pauci-inflammatory phenotype of idiopathic refractory pericarditis.

Changes in perampanel levels during de‐induction: Simulations following carbamazepine discontinuation

ObjectiveTo evaluate the time course of changes in perampanel levels when co‐administered with carbamazepine, and following carbamazepine discontinuation, using a physiologically based pharmacokinetic (PBPK) model.MethodsThe PBPK model was developed, verified using clinical PK data, and used to simulate the effect of abrupt discontinuation and down‐titration (75 mg twice daily [bid]/wk) of co‐administered carbamazepine 300 mg bid on the PK of perampanel once daily (qd). Perampanel dose tapering (8‐4 mg) and up‐titration (2‐6 mg) were simulated during abrupt carbamazepine 300 mg bid discontinuation to identify a titration schedule that minimizes changes in perampanel plasma concentrations.ResultsThe PBPK model accurately reproduced perampanel plasma concentration‐time profiles from clinical studies in single‐ and multiple‐dose regimen simulations, including multiple‐dose carbamazepine co‐administration. The time course of return to pre‐induced perampanel levels occurred more slowly following carbamazepine down‐titration (~48 days after first down‐titration) vs abrupt discontinuation (~25 days). Perampanel dose tapering (8‐4 mg) at abrupt carbamazepine discontinuation produced minimal changes in steady‐state concentrations, which returned to the levels observed during carbamazepine co‐administration in ~15 days from the time of carbamazepine discontinuation. When perampanel was up‐titrated in the presence of carbamazepine, return to steady state occurred more slowly when carbamazepine was down‐titrated weekly (~45 days) vs abrupt discontinuation (~24 days).ConclusionThis PBPK model simulated and predicted optimal perampanel dose tapering and up‐titration schedules for maintaining perampanel levels during conversion to monotherapy. These results may guide physicians when managing conversion from perampanel polytherapy with concomitant enzyme‐inducing anti‐seizure medications to monotherapy.

Corticosteriod tapering in patients (Pts) with relapsed or refractory multiple myeloma (RRMM) receiving subcutaneous daratumumab (DARA SC): Part 3 of the open-label, multicenter, phase Ib PAVO Study.

8537 Background: Intravenous DARA (DARA IV) is approved for the treatment of MM. In Part 2 of PAVO, DARA SC, a concentrated, pre-mixed SC co-formulation of DARA and recombinant human hyaluronidase PH20 (rHuPH20), was well tolerated, with a low infusion-related reaction (IRR) rate, and showed consistent serum concentrations and similar efficacy to DARA IV in RRMM pts. In PAVO Part 3, we evaluated the safety of pre- and post-dose corticosteroid tapering during DARA SC administration. Methods: RRMM pts with ≥2 prior lines of treatment, including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), received DARA SC (DARA 1,800 mg + rHuPH20 30,000 U in 15 mL) by manual SC injection per approved IV monotherapy dosing schedule. Pts received a 3-week (wk) tapering schedule (corticosteroid-free by Cycle [C] 1 Day [D] 22), with methylprednisolone (MP) given PO/IV pre-dose (C1D1, 100 mg; C1D8, 60 mg; C1D15, 30 mg) and PO post-dose (C1D1, 20 mg for 2 days; C1D8, 20 mg for 1 day; C1D15, 20 mg for 1 day), or a 2-wk tapering schedule (corticosteroid-free by C1D15), with MP given PO/IV pre-dose (C1D1, 100 mg; C1D8, 60 mg) and PO post-dose (C1D1, 20 mg for 2 days; C1D8, 20 mg for 1 day). Results: Pts (3-wk group, n = 15; 2-wk group, n = 15) received a median of 2 (range: 2-7) prior lines of therapy, with 37% refractory to a PI and an IMiD. The 3-wk and 2-wk groups received a median (range) of 14 (2-19+) and 8 (2-16+) DARA SC doses without corticosteroids, respectively. No IRRs were reported in the 3-wk group. 3 pts (20%) in the 2-wk group experienced IRRs on C1D1 (grade 3 hypertension, grade 2 chills, grade 1 pyrexia, grade 1 oropharyngeal pain, and grade 1 tachycardia). IRRs occurred within 2 h of the first DARA SC administration; no IRRs were reported at later administrations. Most common (≥25%) treatment emergent adverse events (TEAEs) were upper respiratory tract infection (40%) and fatigue and nausea (27% each). Most common (≥5%) grade 3/4 TEAEs were anaemia, lymphopenia, neutropenia, and hypertension (7% each). At median follow-up of 6.8 mo (3-wk group) and 2.4 mo (2-wk group), the overall response rates were 40% (95% CI, 16-68%) and 27% (95% CI, 8-55%) and ≥very good partial response rates were 13% (95% CI, 2-40%) and 7% (95% CI, 0-32%), respectively. Conclusions: Rapid corticosteroid tapering over 2 wks is safe in RRMM pts receiving DARA SC. These data help guide future DARA SC combinations (ie, T-cell redirectors, CAR-T, or checkpoint inhibitors), where limiting concurrent corticosteroids may be preferred. Clinical trial information: NCT02519452 .

SUN-276 Pembrolizumab-Induced Secondary Adrenal Insufficiency Presenting as Severe Hyponatremia in an 80-Year-Old Male

BackgroundPembrolizumab is an anti-programmed death 1 (PD-1) antibody designed to incite an immune response against malignant cells. By virtue of this mechanism of action, its use has given rise to immune-related adverse events including those affecting the endocrine system. Adrenal insufficiency can occur rarely with anti-PD-1 therapy, and symptoms are usually non-specific.Clinical CaseAn 80-year-old male, known case of non-small cell lung cancer stage IV presented with a 2-week history of progressive body weakness with anorexia, shortness of breath and low-grade fever. He had just received the 4th cycle of pembrolizumab prior to the onset of symptoms. Past medical history was significant for hypertension and type 2 diabetes mellitus which were both controlled, and pulmonary tuberculosis with completed treatment.On physical examination, he was drowsy but oriented. He was normotensive (110/70 mmHg) and tachypneic (28 cpm) with rales on both lung fields. Baseline capillary glucose level was 107 mg/dL. Chest radiograph showed hazy opacities in the right upper to middle region. Blood chemistry revealed severe hyponatremia (114 mmol/L, NV 135-145 mmol/L) and low serum osmolality (247 mOsm/kg, NV 280-300 mOsm/kg). Random (taken 1230H) ACTH and cortisol were <5.00 pg/mL (NV <46 pg/mL) and 2.00 μg/dL (NV 4.30-22.40 μg/dL), respectively. Such levels were judged to be low in the background of an acute illness. Thyroid function tests were normal – TSH 0.993 μIU/mL (NV 0.55-4.78 uIU/mL), FT3 3.890 pg/mL (2.30-4.20 pg/mL), FT4 1.450 ng/dL (0.89-1.76 ng/dL). Magnetic resonance imaging of the pituitary gland did not show abnormal parenchymal enhancement or enlargement.Pembrolizumab-induced secondary adrenal insufficiency was the most probable cause of the hyponatremia. He was started on IV hydrocortisone, as well as piperacillin-tazobactam for pneumonia. Oxygen support via nasal cannula was given. Feeding via nasogastric tube was decided to ensure nutrition and prevent aspiration. He was transferred to the intensive care unit for careful monitoring. Serum sodium level was corrected gradually, with marked clinical improvement thereafter. Within 48 hours, he was transferred to regular room and oral feeding commenced. Hydrocortisone was shifted to prednisone on discharge, with steroid tapering schedule and close follow-up with endocrinologist advised.ConclusionWe presented a case of secondary adrenal insufficiency which likely resulted from hypophysitis induced by pembrolizumab. Hypophysitis following anti-PD1 treatment occurs in <1% of patients on immunotherapy. In such cases, ACTH deficiency is usually isolated and pituitary imaging is frequently normal. Since more patients are being placed on immune-checkpoint inhibition, clinicians should be vigilant for these adverse events, particularly the endocrinopathies which may have non-specific symptoms and may be irreversible.

Axial Spondyloarthritis in the Era of Precision Medicine.

In axial spondyloarthritis (axSpA), the first treatment step is generally a nonsteroidal anti-inflammatory drug, and if insufficient, a biologic is added. Currently, most evidence is available of the biologic tumor necrosis factor-α inhibitors. In patients who have achieved sustained low disease activity, tumor necrosis factor-α inhibitor tapering is considered, although standardized tapering schedules are lacking. In axSpA patients with extra-articular manifestations, the effect of axSpA treatment on these extra-articular manifestations is important to determine the preferred therapy. Overall, it is recommended that treatment of axSpA be individualized based on the most prominent symptoms and presence of extra-articular and peripheral symptoms.

Implementation of a patient-specific tapering protocol at discharge decreases total opioid dose prescribed for 6 weeks after elective primary spine surgery

Background and objectivesAt our institution, we developed an individualized discharge opioid prescribing and tapering protocol for joint replacement patients and implemented the same protocol for neurosurgical spine patients. We then...

To continue or not to continue? Antipsychotic medication maintenance versus dose-reduction/discontinuation in first episode psychosis: HAMLETT, a pragmatic multicenter single-blind randomized controlled trial

BackgroundAntipsychotic medication is effective for symptomatic treatment in schizophrenia-spectrum disorders. After symptom remission, continuation of antipsychotic treatment is associated with lower relapse rates and lower symptom severity compared to dose reduction/discontinuation. Therefore, most guidelines recommend continuation of treatment with antipsychotic medication for at least 1 year. Recently, however, these guidelines have been questioned as one study has shown that more patients achieved long-term functional remission in an early discontinuation condition—a finding that was not replicated in another recently published long-term study.Methods/designThe HAMLETT (Handling Antipsychotic Medication Long-term Evaluation of Targeted Treatment) study is a multicenter pragmatic single-blind randomized controlled trial in two parallel conditions (1:1) investigating the effects of continuation versus dose-reduction/discontinuation of antipsychotic medication after remission of a first episode of psychosis (FEP) on personal and social functioning, psychotic symptom severity, and health-related quality of life. In total 512 participants will be included, aged between 16 and 60 years, in symptomatic remission from a FEP for 3–6 months, and for whom psychosis was not associated with severe or life-threatening self-harm or violence. Recruitment will take place at 24 Dutch sites. Patients are randomized (1:1) to: continuation of antipsychotic medication until at least 1 year after remission (original dose allowing a maximum reduction of 25%, or another antipsychotic drug in similar dose range); or gradual dose reduction till eventual discontinuation of antipsychotics according to a tapering schedule. If signs of relapse occur in this arm, medication dose can be increased again. Measurements are conducted at baseline, at 3, and 6 months post-baseline, and yearly during a follow-up period of 4 years.DiscussionThe HAMLETT study will offer evidence to guide patients and clinicians regarding questions concerning optimal treatment duration and when to taper off medication after remission of a FEP. Moreover, it may provide patient characteristics associated with safe dose reduction with a minimal risk of relapse.Trial statusProtocol version 1.3, October 2018. The study is active and currently recruiting patients (since September 2017), with the first 200 participants by the end of 2019. We anticipate completing recruitment in 2022 and final assessments (including follow-up 3.5 years after phase one) in 2026.Trial registrationEuropean Clinical Trials Database, EudraCT number 2017-002406-12. Registered 7 June 2017.